PROJECT SUMMARY: OVERALL YALE ADRC The Yale Alzheimer?s Disease Research Center (ADRC) seeks to advance our understanding of Alzheimer?s disease at a cell biological level with the eventual goal of translating laboratory discoveries into novel effective clinical therapies. Seven Cores (Administrative, Clinical, Data, Biomarker, Neuropathology, Imaging and Outreach) and a Research Education Component will work together to achieve this goal. Our unifying theme is a focus on the cell biology of specific neurons, and its disruption in AD, whether measured by genome/proteome-wide methods in Biofluids, imaged diagnostically, manifested clinically in behavioral attributes, detected pathologically in brain tissue at autopsy or observed in cultures of induced pluripotent stem cells. The participation of the seven Cores will accelerate and optimize the ability of individual Research Projects both within and beyond the Yale ADRC to ask and answer specific pathophysiological questions and to translate knowledge to therapies. The breadth of the Core support for particular projects will allow assessments across the heterogeneity of Alzheimer?s disease. The Yale ADRC expects to extend its track record of facilitating Research Projects focused on specific neuronal organelles and specific neuronal subtypes perturbed in disease while making use of human tissue analysis and human subject imaging to evaluate mechanistic hypotheses. The Biomarker Core will develop novel, sensitive and high-throughput mass spectrometry assays and genomic methylation profiles to monitor disease mechanisms. The Imaging Core will develop, integrate and apply novel PET tracers and functional MRI connectivity maps to subjects of the Clinical Core and multiple separately supported Research Projects. A key emphasis will be the translational development of research findings into therapeutic benefit. To support the future strength of Alzheimer?s research, the Yale ADRC will strive to advance the careers of Young Investigators through mentorship from a distinguished Internal Advisory Committee, and through Development Project awards coupled with an extensive educational program developed by the Research Education Component. In addition to collecting clinical data and biospecimens of brain, CSF, DNA, serum, blood cells and iPSCs for analysis by members of the Yale ADRC research team, the Yale ADRC will support other NIH- funded research studies on related topics and contribute materials to national NIA-sponsored research networks. The Outreach Core will connect with the community to provide greater knowledge regarding Alzheimer?s disease and related dementia.